PROJECT SUMMARY Structural Biology & Biophysics Core The goal of the Structural Biology & Biophysics (SBB) Core is to help achieve the overall ADDD CENTER aim of developing high quality lead compounds for novel Alzheimer's Disease (AD) targets (Overall MILESTONE 3). The SBB Core will work in concert with the other Technical Cores to provide computer aided drug design for hit generation and optimization, co-crystallization for structure guided design, and target structural information for Target Enablement Packages (TEPs). The SBB Core will enable the identification of hit molecules by first elucidating unknown structures for prioritized ADDD CENTER targets via x-ray diffraction or cryo-electron microscopy, then utilizing those structures (or already known published structures) to perform computer aided drug design via multiple in silico methods. Prioritized molecules will be synthesized by the MCCB Core and evaluated in target specific in vitro assay flow schemes (ADHTS Core) to complete the iteration cycle. To further aid in the structure activity relationship analysis and hit-to-lead optimization process, co-crystals of the protein target and newly designed small molecule binders will be grown and diffracted. The data will be utilized for structure guided design to optimize interactions between the ligand and protein binding sites. Through the contributions of the SBB Core, rapid progress will be made by ADDD CENTER scientists in optimizing hits into lead molecules through both computational simulations and structural studies that help establish connectivity between molecular design and biological function. The SBB Core is led by Drs. Andrew Mesecar and Markus Lill who are responsible for the two components of the core, crystallography/structure determination and computer aided drug design, respectively. The composition of the SBB Core will primarily consist of graduate and post-doctoral students. Additionally, staff from Purdue's extensive core facilities, including the Macromolecular crystallography and cryo-electron microscopy facility, will support SBB Core activities. The Specific Aims of the SBB Core are: Specific Aim 1: Identification of structure based design-amenable nominated targets. Specific Aim 2: Elucidate target structures to guide drug discovery activities. Specific Aim 3: Predict and design potential hit molecular structures for iterative molecular design, synthesis, and testing.